Teratogenicity of etretinate during early pregnancy in the rat and its correlation with maternal plasma concentrations of the drug

Abstract

Sprague‐Dawley female rats were treated with a single oral dose of 0 (vehicle), 10, or 25 mg/kg of etretinate (ET), an aromatic retinoid, on gestation day 6, 7, or 8. While treatment on day 8 with both dosages of ET was highly teratogenic, no evidence of embryotoxicity, considered to be treatment related, was observed when the same doses were administered on day 6 or 7. We concluded that the rat embryo is not susceptible to teratogenic effects of ET on gestation day 6 or 7 and that day 8 is the earliest susceptible period for ET teratogenesis. This may well be true of retinoids as a class since we have observed similar results for all‐trans‐ and 13‐cis‐retinoic acids (unpublished findings). In another study, mated rats were treated with a single oral dose of ET on day 8. No evidence of embryotoxicity was observed at dosages of 1, 3, and 6 mg/kg; in contrast, treatment with 10, 15, or 25 mg/kg of ET resulted in an increasingly greater number of malformed fetuses and resorptions. Plasma concentrations of ET and three metabolites [acitretin (AC), 13‐cis‐etretinate (13‐cis‐ET), and 13‐cis‐acitretin (13‐cis‐AC)] were determined in mated rats given a single oral non‐teratogenic (3 or 6 mg/kg) or teratogenic (10 or 25 mg/kg) dose of ET on gestation day 8. The AUC_0→24hr values of ET and AC, the major metabolite and suspected proximal teratogen, were roughly proportional to the administered dose. The data suggest that a teratogenic response would not be expected in rats after a single dose on gestation day 8 unless the plasma concentrations of ET or AC exceeded 400 and 600 ng/ml, respectively. Plasma concentrations of ET and metabolites were also determined after 3 weeks of multiple dosing of 5 or 10 mg/kg of ET to nonpregnant rats. The AUC value of ET was twofold higher after the high‐dose regimen than after the low‐dose regimen, while the AUC values of the three metabolites were only 1.2 to 1.5 times higher. Multiple dosing resulted in accumulation (2–3–fold) of ET, 13‐cis‐ET, and 13‐cis‐AC, while no accumulation of AC was observed.